1. Academic Validation
  2. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument

Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument

  • Bioorg Med Chem Lett. 2016 Oct 1;26(19):4837-4841. doi: 10.1016/j.bmcl.2016.08.010.
Pascal Furet 1 Keiichi Masuya 2 Joerg Kallen 2 Thérèse Stachyra-Valat 2 Stephan Ruetz 2 Vito Guagnano 2 Philipp Holzer 2 Robert Mah 2 Stefan Stutz 2 Andrea Vaupel 2 Patrick Chène 2 Sébastien Jeay 2 Achim Schlapbach 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland. Electronic address: pascal.furet@novartis.com.
  • 2 Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
Abstract

The p53-MDM2 interaction is an Anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in Cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.

Keywords

Anticancer agents; Protein–protein interaction inhibitors; Structure-based design; p53–MDM2 inhibitors.

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